Mitochondrial μ-calpain is not involved in the processing of apoptosis-inducing factor

Aashish Joshi, Vimala Bondada, James W. Geddes

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38 Scopus citations


Caspase-independent cell death, an important death pathway in many cells including neurons, is executed via apoptosis-inducing factor (AIF), an oxidoreductase, localized to the mitochondrial intermembrane space. AIF is processed and released from mitochondria following mitochondrial permeability transition pore (mPTP) formation, and translocates to the nucleus to induce DNA fragmentation and cell death. The release of AIF requires cleavage of its N-terminus anchored in the inner mitochondrial membrane. The protease responsible for this AIF truncation has not been established, although there is considerable evidence suggesting a role for μ-calpain. We previously found that a pool of μ-calpain is localized to the mitochondrial intermembrane space, the submitochondrial compartment in which AIF truncation occurs. The close submitochondrial proximity of mitochondrial μ-calpain and AIF gives support to the hypothesis that mitochondrial μ-calpain may be the protease responsible for processing AIF prior to its release. In the present study, AIF was released from rat liver mitochondria following mPTP induction by atractyloside. This release was inhibited by the cysteine protease inhibitor MDL28170, but not by more specific calpain inhibitors PD150606 and calpastatin. Atractyloside caused swelling in rat brain mitochondria, but did not induce AIF release. In a mitochondrial fraction from SH-SY5Y neuroblastoma cells, incubation with 5 mM Ca2+ resulted in the activation of μ-calpain but not in AIF truncation. In summary, the localization of μ-calpain to the mitochondrial intermembrane space is suggestive of its possible involvement in AIF processing, but direct experimental evidence supporting such a role has been elusive.

Original languageEnglish
Pages (from-to)221-227
Number of pages7
JournalExperimental Neurology
Issue number2
StatePublished - Aug 2009

Bibliographical note

Funding Information:
This research was supported by NIH grants PO1NS058484, PO1AG010836, and P30NS051220, as well as funding from the Kentucky Spinal Cord and Head Injury Research Trust.


  • Apoptosis
  • Caspase
  • Cell death
  • Cysteine
  • Necrosis
  • Protease

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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